Vanadium and other transition metals are listed as inorganic superfund target chemicals, known to have toxic health effects, and found at Superfund Sites. Inhalation is the usual route of entry into the human body for these chemicals. The ultimate chemical species of metal to enter cells relates to its chemical form in environmental particles as well as the fluid media encountered in tissues. Fuel oil ash is a frequent source of transition metal pollutants at supr fund sites. Several important observations have emerged in our studies to date: Namely, 1) Inhalation of fly ash particles results in both entry into pulmonary cells with constituent interactions in the lung as well as documented entry of metal particles into cells in other organs; 2) Cell responses such as induction of pro-inflammatory chemokines are observed in the lung as well as other organs, most notably the heart; and 3) Functional changes in the heart, as measured with the electrocardiogram, indicate an increasing tendency toward life threatening cardiac electrical vulnerability. Although relatively soluble forms of inhaled particles are expected to easily pass from the pulmonary surface to lymphatics and blood and thus by systemically distributed, the route(s) by which particulate forms may be systemically distributed is less clear. Indeed, recent speculation suggests that the irritant toxicity of the inhaled particles may cause an increase in translocation of particles to the systemic circulation. Studies in the renewal of this project will focus upon mechanisms of particle translocation from the lung and critical responses to these particles by the heart and other organs of the body. Specific aims of this project are: 1) To determine mechanisms of cardiac responses to inhalation of metal-rich fuel oil ash and to determine the relationship of these mechanisms to the electrocardiographic abnormalities observed in exposed animals; and 2) To quantify the translocation of radioactive trace particles form the lung to the heart and other systemic locations and to determine role of fly ash constituents in facilitating this process. Biochemical, physiologic, and molecular approaches will be used to define mechanisms of toxicity. The novel application of these sophisticated technologies in our proposed studies will offer new insights into mechanisms of toxicity of transition metals in fuel oil ash.